MeCP2 and Histone Deacetylases 1 and 2 in Dorsal Striatum Collectively Suppress Repetitive Behaviors

Class I histone deacetylases (HDACs), HDAC1 and HDAC2 often associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined the functional redundancy of HDAC1 and HDAC2 in mature brain. We demonstrate that postnatal forebrain-specific deletion of both HDAC1 and HDAC2 in mice impacts neuronal survival and results in an excessive grooming phenotype caused by dysregulation of the obsessive-compulsive disorder-implicated gene SAP90/PSD-95-associated protein 3 (SAPAP3) in striatum. Moreover, HDAC1- and HDAC2-dependent regulation of SAPAP3 expression requires Mecp2, the gene involved in the pathophysiology of Rett syndrome. We show that postnatal forebrain-specific deletion of Mecp2 causes excessive grooming, which is rescued by restoring striatal Sapap3 expression. Our results provide novel insight into the upstream regulation of SAPAP3, and establish the essential role of striatal HDAC1, HDAC2, and MeCP2 for suppression of repetitive behaviors.